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SMOKING, CHROMOSOME DAMAGE AND AN ABNORMAL DNA DAMAGE RESPONSE IN HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC)

Flores Obando, Rafael Ernesto (2009) SMOKING, CHROMOSOME DAMAGE AND AN ABNORMAL DNA DAMAGE RESPONSE IN HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC). Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Smoking is one of the leading risk factors that contribute to the development of head and neck squamous cell carcinoma (HNSCC). Smoking induces chromosome breaks. One of the most frequent and earliest alterations in HNSCC is the segmental loss of the short arm of chromosome 3 (3p). Another frequent observation is the activation of one of the most common fragile sites in HNSCC, FRA3B, which spans the FHIT gene, considered to be a tumor suppressor. Distal to FHIT is FANCD2, which encodes a protein required for the proper function of the Fanconi anemia/BRCA pathway and eventual repair of DNA damage through homologous recombination repair. Recently, it has been observed that FANCD2 gene and protein expression is decreased in HNSCC cells. Therefore, we hypothesize that 3p loss, resulting from the activation of the fragile site FRA3B, leads to FANCD2 gene copy loss and a defective DNA damage response. Western blots showed decreased expression of FHIT protein in HNSCC cell lines. Fluorescence in situ hybridization revealed partial loss of FANCD2 in HNSCC cell lines studied. Western blotting and quantitative RT-PCR showed decreased FANCD2 protein and gene expression in HNSCC cell lines with FANCD2 gene copy loss. HNSCC cell lines with decreased FHIT protein expression, FANCD2 gene copy loss, and decreased FANCD2 gene and protein expression exhibited decreased FANCD2 and RAD51 focus formation. Our results suggest that smoking could induce breakage of the fragile site, FRA3B, leading to FANCD2 loss and resulting in defective DNA damage repair. The use of targeted therapy on cancer cells with deficient DNA damage repair, like CHEK1 small molecule inhibitors, could improve the currently available cancer treatment schemes. The public health relevance of our studies involves the use of an abnormal FA/BRCA pathway as a marker for selective use of targeted cancer therapy for HNSCC.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Flores Obando, Rafael Ernestoe_flores_nica@yahoo.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGollin, Susanne M.gollin@pitt.eduGOLLIN
Committee MemberFerrell, Robert E.rferrell@pitt.eduRFERRELL
Committee MemberSaunders, William S.wsaund@pitt.eduWSAUND
Date: 28 September 2009
Date Type: Completion
Defense Date: 29 May 2009
Approval Date: 28 September 2009
Submission Date: 9 June 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: 3p deletion; FA/BRCA pathway; FANCD2; FHIT; FRA3B; HNSCC
Other ID: http://etd.library.pitt.edu/ETD/available/etd-06092009-153339/, etd-06092009-153339
Date Deposited: 10 Nov 2011 19:46
Last Modified: 15 Nov 2016 13:44
URI: http://d-scholarship.pitt.edu/id/eprint/8054

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